Preclinical studies have shown that basic fibroblast growth factor (bFGF), an angiogenic peptide, promotes collateral development in models of myocardial and hind limb ischemia. We assessed the safety of intra-arterial bFGF in patients with intermittent claudication, and studied its effects on calf blood flow. A double-blind, placebo-controlled, dose-escalation trial was conducted in claudication patients with ankle/brachial systolic index <0.8. Patients were randomly assigned to placebo (n=6), 10 mcg/kg of bFGF (provided by Scios, Inc., Mountainview, CA) (n=4), 30 mcg/kg of bFGF once (n=5) and 30 mcg/kg of bFGF twice (n=4). The study drug was infused into the femoral artery of the ischemic leg. Calf blood flow was measured with strain gauge plethysmography in the final 2 treated groups and in 4 placebo patients, prior to treatment, and at 1 and 6 months after treatment. Subjective changes in the degree of claudication were assessed by a questionnaire. Intra arterial bFGF was well tolerated. bFGF significantly improved calf blood flow at 1 month by 66 +/- 26% (mean +/- SEM), and at 6 months by 153 +/- 51% (n=9, P=0.002). The magnitude of increase in calf blood flow was greater in patients receiving 2 doses of bFGF compared to 1 dose of 30 mcg/kg. Flow did not change significantly in the placebo group. bFGF-treated patients reported subjective improvement in symptoms of claudication, in contrast to placebo patients. In patients with intermittent claudication, 2 intra-arterial doses of 30 mcg/kg bFGF are safe. Although a larger confirmatory trial is necessary, our results provide the first proof of concept in a randomized double-blinded, placebo-controlled trial that angiogenic therapy can result in enhanced collateral flow in patients with obstructive peripheral arterial disease.